1. Field of the Invention
The present invention relates generally to the fields of immunology and tumor biology. More specifically, the present invention relates to treatment for the enhancement of CD38 protein expression in target tumor cells to increase the cytotoxicity of anti-CD38 based immunotoxins.
2. Description of the Related Art
The use of monoclonal antibodies for delivering drugs or toxins to distinct molecular structures expressed on the surface of unwanted tumor cells represents an attractive and potentially useful strategy. Theoretically, such a targeted approach to cancer therapy could offer a major advance in the selective elimination of tumor cells while reducing the toxicity of treatment towards normal non-target tissues. Nevertheless, in practice many problems exist that need to be addressed before immunotoxin or antibody-drug therapies can be truly effective in vivo.
One potential limitation to the success of any targeted approach to therapy is the heterogeneity of target antigen expression within a population of tumor cells. It follows that if a small number of cells within a tumor were negative for the target antigen or expressed the antigen only very weakly, then these cells could possibly escape destruction due to a failure of antibody-mediated delivery of the cytotoxic agent to those particular cells. A possible means of overcoming this problem would be to identify agents that induce high levels of cell surface target molecules, in the expectation that target tumor cells which were antigen negative would express these target molecules in abundance.
All-trans-retinoic acid (RA) is an agent that induces high levels of CD38 cell surface antigen expression in several myeloid and lymphoid leukemia cells. Retinoic acid-induced expression of CD38 in these cells is specific, rapid, dose-dependent, and highly sensitive, with 4-fold induction at as low a dose of retinoic acid as 10−13 M. The induction of CD38 expression by retinoic acids has been shown to involve the RARα retinoid receptor. RAR receptors form heterodimers with RXR receptors; the RXR/RAR heterodimer then interacts with DNA sequences known as retinoic acid response elements (RARE's) which are involved in retinoid-induced transcription.
CD38 is a 45-kDa cell surface protein which is primarily expressed by early progenitor and mature activated cells of the hematopoetic system. It is a transmembrane glycoprotein with a short N-terminal cytoplasmic domain and a long C-terminal extracellular domain. The extracellular domain has been shown to be a bifunctional enzyme having ADP-ribosyl cyclase as well as ADP-ribosyl hydrolase activities in that it catalyzes the conversion of NAD+ to cADPR (cyclase) and can further hydrolyze it to ADP-ribose (hydrolase). cADPR is involved in the mobilization of calcium from intracellular stores which is a second messenger activity important for cellular proliferation, differentiation, and apoptosis. CD38 is believed to act as a receptor for an unidentified ligand and to act as a cell adhesion molecule by interacting with CD31. Experiments in which CD38 function was activated by monoclonal antibodies directed against it have implicated CD38 in proliferation of mature B lymphocytes and myeloid leukemia cells, rescue of germinal center cells from apoptosis, and growth suppression of stroma-supported cultures of B-cell progenitors as well as induction of the cytokines IL-6, IGN-g, GM-CSF, and IL-10. In addition, it has been shown to signal an increase in TNF-α, IL-1, IL-6, and IL-8 transcription in myeloid leukemia cells.
The prior art is deficient in the lack of a method to induce the expression of a target molecule for immunotherapy of tumor and other disease-causing cells. The present invention fulfills this longstanding need and desire in the art.